Antibody-drug conjugates (ADCs) and bispecific antibodies (bsAbs) are two advanced classes of antibody-based therapeutics.
They have distinct molecular architectures and mechanisms of action that fundamentally shape their clinical applications.
ADCs are composed of a monoclonal antibody (typically humanized or fully human IgG) covalently linked to a cytotoxic payload via a chemical linker.
The antibody moiety confers specificity by binding to a tumor-associated antigen, while the linker is engineered to be stable in systemic circulation but cleavable within the target cell, ensuring that the cytotoxic payload is released only after internalization and lysosomal trafficking.
The drug-to-antibody ratio (DAR), conjugation site, and linker chemistry are critical determinants of ADC pharmacokinetics, efficacy, and safety.
Novel payloads have expanded the spectrum of cytotoxic mechanisms available for tumor cell killing.
In contrast, bsAbs are engineered immunoglobulins capable of simultaneously binding two distinct antigens or epitopes, either on the same or different cells.
This dual specificity is achieved through various molecular formats, including full-length IgG-like bsAbs with modified heavy and light chains, single-chain variable fragments (scFv), tandem diabodies, and other recombinant constructs.
The most clinically advanced bsAbs are those that bridge immune effector cells ( such as T cells or NK cells) to tumor cells by binding CD3 on T cells and a tumor-associated antigen, thereby facilitating immune-mediated cytotoxicity.
Other bsAbs are designed to block two signaling pathways or to enhance tumor cell internalization for drug delivery.
The mechanism of action of ADCs is predicated on targeted delivery of a cytotoxic agent.
Upon intravenous administration, the ADC binds to the target antigen on the surface of tumor cells, triggering internalization and lysosomal degradation, which releases the cytotoxic payload to induce apoptosis.
The selectivity of ADCs for tumor cells is determined by the expression profile of the target antigen, the affinity of the antibody, and the stability of the linker.
Off-target toxicity can occur if the antigen is expressed on normal tissues or if the linker is prematurely cleaved in circulation.
BsAbs, by contrast, exert their effects primarily through immune cell recruitment and activation.
T-cell-engaging bsAb binds a tumor-associated antigen on malignant cells and the CD3 subunit on T cells, bringing T cells into close proximity with tumor cells and resulting in T-cell activation, degranulation, and targeted cytolysis.
This mechanism is independent of major histocompatibility complex (MHC) restriction and does not require prior antigen presentation, making bsAbs effective even in tumors with low immunogenicity.
Other bsAbs block two signaling pathways simultaneously, thereby overcoming compensatory mechanisms of drug resistance or tumor heterogeneity.
Bispecific ADCs (bsADCs), combine the dual-targeting capability of bsAbs with the cytotoxic payload delivery of ADCs.
These constructs are designed to enhance specificity, internalization, and antitumor activity, particularly in heterogeneous or resistant tumors, and are currently in clinical development.
As of January 2026, at least 15 ADCs and more than 10 bsAbs have received FDA approval for a range of hematologic and solid malignancies.
ADCs are approved for both hematologic and solid tumors, including:
HER2-positive metastatic and early breast cancer (trastuzumab emtansine, trastuzumab deruxtecan)
Triple-negative and HR+/HER2- metastatic breast cancer (sacituzumab govitecan, datopotamab deruxtecan)
HER2-mutant and c-Met+ non-small cell lung cancer (trastuzumab deruxtecan, telisotuzumab vedotin)
FRα-positive platinum-resistant ovarian cancer (mirvetuximab soravtansine)
Recurrent/metastatic cervical cancer (tisotumab vedotin)
Locally advanced/metastatic urothelial carcinoma (enfortumab vedotin)
Classical Hodgkin lymphoma, systemic anaplastic large cell lymphoma, peripheral T-cell lymphomas, and cutaneous T-cell lymphomas (brentuximab vedotin)
Relapsed/refractory diffuse large B-cell lymphoma (polatuzumab vedotin, loncastuximab tesirine)
CD33-positive acute myeloid leukemia (gemtuzumab ozogamicin).
BsAbs are primarily approved for hematologic malignancies, with recent expansion into select solid tumors:
CD19-positive B-cell precursor acute lymphoblastic leukemia (blinatumomab)
Relapsed/refractory diffuse large B-cell lymphoma (epcoritamab, glofitamab)
– Relapsed/refractory follicular lymphoma (mosunetuzumab, epcoritamab)
– Relapsed/refractory multiple myeloma (teclistamab)
– EGFR-mutated NSCLC (amivantamab)
– HER2-positive biliary tract cancer (zanidatamab)
– NRG1 fusion-positive NSCLC and pancreatic cancer (zenocutuzumab)
– HLA-A02:01-positive unresectable/metastatic uveal melanoma (tebentafusp)
– Relapsed/refractory small cell lung cancer (tarlatamab).
A summary table of FDA-approved ADCs and bsAbs, including targets, indications, and references, is provided below.
Patient selection for ADCs is typically biomarker-driven, with eligibility contingent on the presence and quantification of a target antigen, as well as disease subtype and prior therapy.
Trastuzumab emtansine and trastuzumab deruxtecan require HER2 overexpression or amplification as determined by FDA-approved companion diagnostics.
Mirvetuximab soravtansine requires high FRα expression (≥75% of tumor cells with ≥2+ staining by IHC), and telisotuzumab vedotin requires c-Met overexpression (≥50% of tumor cells with strong (3+) staining).
Sacituzumab govitecan does not require demonstration of TROP2 expression, reflecting the broad expression of TROP2 in breast cancers.
Eligibility criteria for ADCs may include disease stage, prior lines of therapy, performance status, and organ function.
Datopotamab deruxtecan is approved for EGFR-mutated NSCLC after prior EGFR-directed therapy and platinum-based chemotherapy, and for HR+/HER2- breast cancer after prior endocrine and chemotherapy.
BsAbs, particularly those used in hematologic malignancies, are generally less dependent on quantitative antigen expression and more focused on disease phenotype and prior therapy.
Blinatumomab is approved for CD19-positive B-cell precursor ALL, with eligibility based on the presence of CD19 on leukemic blasts, as determined by flow cytometry or IHC, but without a minimum threshold of CD19 expression.
Teclistamab is indicated for relapsed/refractory multiple myeloma after at least four prior lines of therapy, with eligibility based on disease phenotype rather than BCMA expression level.
In solid tumors, bsAbs may require demonstration of specific molecular alterations, such as HLA-A02:01 positivity for tebentafusp or EGFR exon 20 insertion mutations for amivantamab.
Unlike ADCs, bsAbs do not generally require high antigen density for efficacy, as immune redirection can occur even with low-level antigen expression, provided the antigen is present and accessible.
Antigen loss or modulation is a recognized mechanism of resistance and a contraindication to bsAb therapy.
Eligibility criteria for bsAbs also include considerations of immune competence, as profound immunosuppression may limit efficacy and increase the risk of infection or immune-related toxicities.
In relapsed/refractory multiple myeloma, both ADCs and bsAbs targeting BCMA have shown substantial activity.
ADCs have achieved overall response rates (ORR) ranging from 34% to 60%, with complete response (CR) rates of 3% to 6%.
Bispecific T-cell engagers in the same setting have demonstrated ORRs from 31% to 83%, with CR rates of 7% to 22%.
bsAbs may offer superior potency, maximal cell killing, and consistency across patient samples compared to ADCs.
In B-cell lymphomas, bsAbs such as blinatumomab, mosunetuzumab, and glofitamab have produced deep and durable responses in heavily pretreated patients, with high rates of minimal residual disease negativity in ALL and meaningful response rates in DLBCL and follicular lymphoma.
ADCs such as brentuximab vedotin have also demonstrated significant efficacy in Hodgkin lymphoma and anaplastic large cell lymphoma, both as monotherapy and in combination regimens.
In solid tumors, ADCs have demonstrated high response rates and survival benefits in HER2+ breast cancer (ado-trastuzumab emtansine, trastuzumab deruxtecan), cervical cancer (tisotumab vedotin), and urothelial carcinoma (enfortumab vedotin), with response rates and survival benefits superior to conventional chemotherapy in selected populations.
BsAbs have made slower progress in solid tumors, largely due to challenges in identifying tumor-specific antigens and overcoming the immunosuppressive microenvironment, but agents such as tebentafusp have shown marked activity in uveal melanoma.
Meta-analyses in DLBCL have shown that bsAbs achieve a pooled CR rate of 36%, compared to 51% for CAR T-cell therapy, with a 1-year progression-free survival rate of 32% for bsAbs.
In head and neck squamous cell carcinoma and nasopharyngeal carcinoma, ADC monotherapies achieved ORRs up to 47%, while bsAb monotherapies achieved ORRs of 0–37%.
ADCs are primarily associated with toxicities related to the cytotoxic payload, off-target effects, and the specific antigen targeted.
Meta-analyses indicate that the overall incidence of treatment-related adverse events with ADCs is high, with all-grade AEs occurring in over 90% of patients and grade ≥3 AEs in approximately 46%.
The most common hematologic toxicities include neutropenia (43.7% all-grade, 31.2% grade ≥3), lymphopenia (53.0% all-grade, 21.0% grade ≥3), anemia, and thrombocytopenia (22.6% grade ≥3).
Peripheral neuropathy is a frequent complication, particularly with ADCs containing tubulin-binding agents such as monomethyl auristatin E (MMAE).
Ocular toxicities (e.g., keratopathy, blurred vision) are notable with certain ADCs, such as those targeting BCMA or tissue factor.
Unique toxicities include cardiac dysfunction with HER2-targeting ADCs and hemorrhagic events with tissue factor-targeting agents.
The onset and severity of these toxicities vary by payload, linker chemistry, drug-to-antibody ratio, and patient factors.
BsAbs, particularly T-cell engagers, are most commonly associated with immune-mediated toxicities.
Cytokine release syndrome (CRS) is the hallmark adverse event, occurring in a substantial proportion of patients and ranging from mild to life-threatening.
Any-grade CRS occurs in 16.4% of patients, and ICANS in 11.5%, with only 0.09% requiring tocilizumab.
CRS is characterized by fever, hypotension, hypoxia, and organ dysfunction, and is managed with supportive care and cytokine blockade (tocilizumab).
Immune effector cell-associated neurotoxicity syndrome (ICANS) is another important toxicity, presenting as confusion, aphasia, seizures, or encephalopathy.
Hematologic toxicities, including neutropenia and cytopenias, are also common, reflecting both on-target effects and immune activation.
Infections, including opportunistic pathogens, are a concern due to immunosuppression.
BsAbs may also induce anti-drug antibodies, potentially limiting efficacy and increasing the risk of hypersensitivity reactions.
The risk and severity of these immune-related toxicities are influenced by dosing and patient comorbidities.
In combination regimens, the incidence of specific toxicities may increase: the incidence of interstitial lung disease (ILD)/is higher with trastuzumab deruxtecan plus immune checkpoint inhibitor (15.0%) compared to trastuzumab deruxtecan alone (11.5%).
Treatment discontinuation rates and grade ≥3 adverse events are also higher in combination regimens.
ADCs are characterized by long half-lives, typically ranging from several days to weeks.
ADCs are administered as intermittent intravenous infusions, with dosing intervals ranging from every 1 to 3 weeks. depending on the agent: trastuzumab emtansine is administered at 3.6 mg/kg IV every 3 weeks, while trastuzumab deruxtecan is administered at 5.4 mg/kg IV every 3 weeks for breast cancer and 6.4 mg, respectively.